Most randomized clinical trials are typical phase 3 efficacy trials, where researchers enroll a homogeneous patient population with a long list of inclusion and exclusion criteria, under highly controlled environments, and strictly defined treatment regimens, to show the effect of a drug or an intervention. Although this approach maximizes the possibility of revealing the effect of the treatment, it may limit generalizability of the results to ‘real’ world population in everyday clinical practice.

In this edition of NephJC we will be looking at 2 clinical trials designed to address the important question of utility of IV fluids- Saline vs balanced crystalloids. These are pragmatic trials which are designed and conducted around two or more medical interventions directly relevant to routine clinical practice and to assess their incorporation widely as such.

Pragmatic and efficacy (explanatory) trials represent two ends of a continuum rather than distinct entities. There is no simple threshold and there are hardly few, if any, purely pragmatic or explanatory trials, rather a study may contain elements from both approaches. Much has been written about tools to design a Pragmatic trial, the difference between pragmatic and explanatory trials and their effective use in conducting more balanced clinical trials. Read about an excellent post on this topic from a previous Nephmadness by Perry Wilson.

Pragmatic trials typically tend to measure outcomes which can be easily measured - and maybe part of routine management. All cause mortality is one, cause specific mortality being much more difficult given detailed information required for adjudication. Similarly, ICU stay, or hospital stay are more such examples. Emphasis is placed on easily captured measures of the effects of a disease. In explanatory trials the outcomes tend to be carefully measured biomarkers at specific times, adjudicated composite endpoints and such. More recently, the patient voice and patient related outcome (PRO) measures in drug development have also come into focus and PRO instruments are now increasingly used by trialists to incorporate the patient perspective into clinical trial end points. As an example, PRO instruments are being developed and used in trials in Glomerular diseases.

One major ethical concern regarding pragmatic trials is that the traditional informed consent may make them less practical, reduce generalizability, lower recruitment rates and possibly induce selection bias. Waiver of consent is one of the proposed alternatives to traditional informed consent which was used in the SALT-ED and SMART trials. Thus use of pragmatic trial design made sense here as obtaining informed consent regarding fluid choice and randomization of each individual patient among two different groups is impractical given that time is of essence of rapid fluid administration.

All this does make pragmatic trials slightly less expensive, and allows large numbers to be enrolled. The data generated can be a little noisy however, given the inherent pragmatic nature of its design. Thus they answer a different question: rather than ‘will using Ringer’s lactate in this patient reduce the risk of acute kidney injury?’ they provide information for a different question ‘will using Ringer’s lactate for all patients in the Emergency department reduce the overall average hospital stay?’

We can put a long list of robust clinical trials published in recent years- ASTRAL/CORAL, SPRINT, REPRISE, ACTIVE and more, which have come under some criticism regarding aspects which are applicable to real world population (e.g.- efficacy or cost-effectiveness) or some other trials which have shown drug efficacy in treating conditions but there are concerns about safety e.g.- increased mortality due to infections in TESTING trial or amputation risk in CANVAS trial.

The amount of grey matter, labor and hard work which goes behind successfully conducting a clinical trial is tremendous. The goal is always to come out at the other end of the tunnel with results which are hopefully meaningful and strongly support health care decisions or interventions that will improve outcomes for patients and the public. The aim is to push every aspect of health care delivery to the highest level of evidence based medicine, and what happens behind the scenes during the phase of trial designing is the first step towards that goal.